Elsevier

Obesity Research & Clinical Practice

Volume 10, Issue 6, November–December 2016, Pages 710-718
Obesity Research & Clinical Practice

The relationship between aquaglyceroporin expression and development of fatty liver in diet-induced obesity and ob/ob mice

https://doi.org/10.1016/j.orcp.2015.12.001Get rights and content

Summary

Aquaporin (AQP) 7 and AQP9 are subcategorised as aquaglyceroporins which transport glycerin in addition to water. These AQPs may play a role in the homeostasis of energy metabolism. We examined the effect of AQP7, AQP9, and lipid metabolism-related gene expression in obese mice. In diet-induced obese (DIO) mice, excess lipid accumulated in the liver, which was hyperleptinemic and hyperinsulinemic. Hepatic AQP9 gene expression was significantly increased in both DIO and ob/ob mice compared to controls. The mRNA expression levels of fatty acid and triglyceride synthesis-related genes and fatty acid β oxidation-related genes in the liver were also higher in both mouse models, suggesting that triglyceride synthesis in this organ is promoted as a result of glycerol release from adipocytes. Adipose AQP7 and AQP9 gene expressions were increased in DIO mice, but there was no difference in ob/ob mice compared to wild-type mice. In summary, adipose AQP7 and AQP9 gene expressions are increased by diet-induced obesity, indicating that this is one of the mechanisms by which lipid accumulates in response to a high fat diet, not the genetic mutation of ob/ob mice. Hepatic AQP9 gene expression was increased in both obesity model mice. AQP7 and AQP9 therefore have the potential of defining molecules for the characterisation of obesity or fatty liver and may be a target molecules for the treatment of those disease.

Introduction

Obesity increases the risk of developing diabetes, fatty liver, hypertension, hyperlipidemia, metabolic syndrome, coronary heart disease, and stroke [1], [2], and preventing this condition is important in the healthy maintenance of the body. Obesity is the state in which surplus energy accumulates as fat as a result of excessive energy intake and low energy expenditure due to lack of exercise. The adipose tissue undergoes lipogenesis and lipolysis depending on the energy balance. In the hypertrophic state, the adipocytes store triglycerides, whereas in response to starvation and sympathetic nerve activation, they degrade triglycerides and release free fatty acids (FFA) and glycerol into the blood to supply energy to the entire body [3], [4].

Aquaporins (AQPs) are channels that allow the movement of water across the cell membrane [5]. Certain members of this family, the aquaglyceroporins, which include AQP3, 7, 9, and 10, transport glycerol as well as water and are involved in the biosynthesis of triglycerides [6]. The AQP7 gene was first cloned from human adipose tissue [7]. AQP7 is localised to a wide range of tissues in rodents. It is abundantly expressed in adipose tissue [8], and is also expressed in kidney, pancreas, and muscle [9], [10]. The AQP9 gene was first cloned from a human liver cDNA library [11]. In rats, AQP9 mRNA has been found in the liver, testis, brain, and lung [12].

The FFA and glycerol generated in adipocytes are released to other tissues, and the efflux of glycerol from adipose tissue is facilitated by AQP7 [13], [14], [15], [16]. In the liver AQP9 facilitates the uptake of glycerol, which is metabolised to glycerol 3-phosphate via the glycolytic pathway [13], [14], [15], [16]. Hence, both AQP7 and AQP9 seem to play an important role in the homeostasis of energy metabolism. The expression levels of these genes in adipocytes and hepatocytes are reduced by feeding and increased by fasting, in parallel to the changes in plasma glycerol levels [7], [17]. In rodents, AQP7 expression in the adipose tissue and AQP9 expression in the liver are down-regulated by insulin. Streptozotocin (STZ)-induced diabetic mice exhibit increased expression levels of adipocyte AQP7 and hepatic AQP9 [18], [19], [20]. In addition, the gene expression of adipocyte AQP7 and hepatic AQP9 are increased in leptin receptor deficient db/db mice [20]. Recently, we demonstrated that AQP7 expression is upregulated in the skeletal muscle of leptin deficient ob/ob mice [21]. Many reports have described the function and regulation of the aquaglyceroporins in ob/ob and db/db mice as models of obesity, but there have been fewer studies of diet-induced obese (DIO) mice. Here we investigated the AQP gene expression profiles of DIO and ob/ob mice, and examined the role of AQP7 and AQP9 in their lipid metabolism.

Section snippets

Animals and diets

Male C57BL/6J mice were obtained from Sankyo Labo Service Corporation (Tokyo, Japan) at 5 weeks of age and fed a normal laboratory diet for 1 week to acclimatise the animals to their new conditions. The mice were divided into 2 groups (lean or DIO group, n = 7 in each group). At the beginning of experiment, body weight was the same between the two groups (lean group; 20.4 ± 0.63 g vs DIO group; 20.6 ± 0.56 g (p = 0.999)). Mice in the lean control group were fed a normal laboratory diet (Labo MR stock;

Body weight and tissue weight

The body and WAT weights of the DIO mice increased 1.5-fold and 8.6-fold, respectively, compared with those of lean mice (Table 2). These results suggest that the increase in body weight of the DIO mice is due to an increase in adipose tissue weight. Liver weights were significantly increased in the DIO mice.

Blood glucose and plasma parameters

In comparison with lean mice, DIO mice displayed significantly elevated levels of blood glucose and plasma insulin (Table 2). The plasma leptin level was also approximately 37-fold higher

Discussion

This study investigated the role of AQP7 and AQP9 in the development of obesity and fatty liver in obese DIO and ob/ob mice. Body weights and epididymal WAT weights were significantly increased in these mice compared with lean mice. In addition, DIO mice displayed significantly elevated levels of blood glucose and plasma insulin. In particular, there was a dramatic increase in plasma leptin levels in these mice. Moreover, the lipid accumulation in their liver was significantly increased. It has

Conflict of interest

No potential conflicts of interest were disclosed.

Acknowledgments

This work was supported in part by a Research Grant from the Asahi Group Foundation to Y.W. and a Grant-in-Aid for Scientific Research on Innovative Areas (to SS no. 22126004) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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